1. Field of the Invention
This invention relates to novel isomers of bufalin and resibufogenin and their glycosides. In particular, this invention relates to the preparation of these compounds and their use in the treatment of various heart diseases.
2. Description of Prior Art
Bufalin and resibufogenin are examples of compounds within the class of compounds known as aglycones, or genins. The aglycones are steroid derivatives which exert a strong, specific action on the heart muscle in man or animals; they are consequently characterized as being cardiac-active or cardiotonic. These compounds have found important use, particularly in their glycosidic form, in the treatment of heart diseases by, for instance, exerting a beneficial stimulation to a diseased heart. The glycosides are known as cardiac glycosides.
The aglycones are characterized by a steroid nucleus with methyl substituents at the 10 and 13 positions, a hydroxy substituent normally at the 14 position, and a substituent at the 17 position which is either a five-membered .alpha.,.beta. unsaturated lactone ring or a six-membered, twice-unsaturated lactone ring. The steroid nucleus is of the cis-decalin type, with trans B/C ring structure and cis C/D ring structure. The hydroxy groups and methyl groups are .beta. oriented.
The aglycones containing the five-member lactone substituent are known as cardenolides. A description of certain cardenolides and their preparation is found in U.S. Pat. No. 4,259,240, entitled "Synthesis of Furyl Intermediates, and Cardenolides and Their Isomers Prepared Therefrom," the disclosure of which is incorporated herein by reference. Cardenolides occur naturally in plants. Digitalis, for instance, is a mixture of cardenolide glycosides which, upon hydrolysis, affords a mixture of cardenolides, including digitoxigenin, digoxigenin and gitoxigenin.
Digitalis preparations have been used in the treatment of heart disease for more than 200 years. The cardiotonic glycosides contained in these preparations have the ability to slow the heart rate and, at the same time, to increase the contractility of the heart muscle (that is, they display inotropic activity), and thus to improve, in general, the heart function. The inotropic effect, on the biochemical level, is connected to the release of calcium. Because of these characteristics, the glycosides of digitalis are among the top ten most prescribed drugs.
The aglycones containing the six-member lactone substituents are known as bufadienolides. They occur naturally in plants and animals, and, like the cardenolides, possess high inotropic activity. Bufalin is a bufadienolide found naturally in certain toads, the formula of which, identical in nuclear structure to digitoxigenin, is shown below. ##STR1## Resibufogenin, shown below, also a naturally occurring bufadienolide found in certain toads, contains a 14,15 epoxy linkage in place of the 14-hydroxy group. ##STR2##
The aglycones, both cardenolides and bufadienolides, are often found in nature in their glycosidic form, with the aglycone moiety linked to a sugar at the 3-position of the steroid nucleus. The glycosidic form is normally employed in clinical applications, the sugar residue providing favorable solubility and distribution characteristics. Analysis of naturally occurring aglycone glycosides has shown the presence of a large variety of different sugars, including glucose, rhamnose, fucose, talomethlose, antiarose, allomethylose, thevetose, digitalose, acovenose, acofriose, cymarose, sarmentose, oleandrose, diginose, digitoxose, and boivinose.
With respect to methods of preparing and manipulating 17-substituted steroid compounds, U.S. Pat. No. 4,259,240 discloses reaction of a 15,16 unsaturated, 17-keto testosterone derivative to give a 17-.beta.-hydroxy, 17-.alpha.-furyl compound. This compound is subjected to allylic rearrangement to yield a 16,17 unsaturated, 15-hydroxy, 17-.beta.-furyl product. Subsequent steps include saturation of the 16,17 double bond; dehydroxylation of the 15-hydroxy to yield a 14,15 double bond; and addition of a 14-.beta.-hydroxy to the double bond.
With respect to the possibility of converting furanes into six-membered rings, oxidative ring openings of furanes to furanose sugar derivatives and tautomerizations of these to pyranose derivatives are well known in furane and sugar chemistry. However, the ring opening of the 17-furyl substituent of the invention is part of the key to the preparation of the novel isomers, and is unknown in the art.
A major problem with the clinical application of aglycones is the dangerously high toxicity of these compounds. In fact, many of these compounds have found historical use as poisons. In the clinical use of digitalis glycosides, for instance, most patients are given 60% of the toxic dose in order to obtain the desired therapeutic response. As a consequence, the margin of safety is quite narrow and, by some estimates, digitalis glycosides are responsible for one-half of all drug-induced hospital deaths. Bufadienolide glycosides are similarly quite toxic unless administered in carefully controlled dosages.
Another problem in the clinical use of cardiac glycosides is the scarcity, and consequent expense, of many of these compounds. Bufalin, for instance, is currently used clinically even though it has not been synthesized and must be isolated from natural sources at a cost of several thousand U.S. dollars per gram.